Aspects of the development of new anti-Leishmania drugs: from control of neglected infections to parasite-host interactions and drug-resistant parasites

Abstract

Leishmaniasis is a neglected disease caused by parasites of the genus Leishmania. The disease leads to different clinical manifestations determined by parasite features like heterogeneity in the virulence of distinct species-zymodemes and host parameters such as genetic characteristics and immunological status.Visceral leishmaniasis (VL) is the most severe disease form and is potentially fatal if untreated. Drugs in use against VL present several drawbacks including high toxicity, relevant contraindications and complicated administration regimens. In addition, 90% of world's VL cases are concentrated in poorest locations like the Indian sub-continent where a number of factors contribute to an ineffective disease control including access to medicines and its relatively expensive price and the development of resistant Leishmania strains, not only to the classical antimonials drugs but also to miltefosine, the only oral drug available.Therefore, the development of new drugs against VL is urgent and must have in consideration several aspects in order to achieve and be effective to most of the disease cases. Indeed, treatment outcomes vary substantially between different geographic regions and depend on the drug(s) used, drug exposure, severity of disease, host immunity, and the presence of coinfections.So, in order to improve the drug discovery process for anti-leishmanials the drug screening should involve recent clinical isolates of the L. donovani complex, with different susceptibility profiles to existing drugs and from different geographical origin.